Handbook of comparative pharmacokinetics and residues of veterinary antimicrobials

541 Pages·1991·8.12 MB·English

by  Craigmill

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COMPARATIVE
PHARMACOKINETICS
and
RESIDUES VETERINARY ANTIMICROBIALS
of
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Library of Congress Cataloging-in-Publication Data
Riviere, J. Edmond (Jim Edmond)
CRC handbook of comparative pharmacokinetics and residues of
veterinary antimicrobials / authors, J. Edmond Riviere, Arthur L.
Craigmill, Stephen F. Sundlof.
p. cm.
Includes bibliographical references.
ISBN 0-8493-3211-7
1. Anti-infective agents in veterinary medicine -- Pharmacokinetics-
Handbooks, manuals, etc. 2. Veterinary drug residues -- Handbooks, manuals,
etc. 3. Animal food -- Contamination -- Handbooks, manuals,
etc. I. Craigmill, Arthur L. II. Sundlof. Stephen Frederick,
1951- . III. Title.
SF918.A48R58 1990 90-32263
636.089’57--dc20
A Library of Congress record exists under LC control number: 90032263
Publisher’s Note
The publisher has gone to great lengths to ensure the quality of this reprint but points out that some imperfections in the original copies may be apparent.
Disclaimer
The publisher has made every effort to trace copyright holders and welcomes correspondence from those they have been unable to contact.
ISBN 13: 978-1-315-89195-8 (hbk)
ISBN 13: 978-1-351-07105-5 (ebk)
Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the
CRC Press Web site at http://www.crcpress.com
FOREWORD the pharmacokinetic analyses are performed and the computer software is
written.
Information contained in FARAD proved to be most helpful in managing
an extensive residue problem associated with food animals ingesting feed
Human food safety is the foremost consideration in food animal produc- contaminated with heptachlor in the Midwest during 1986. It was possible to
tion. This consideration supercedes even the obvious importance of economic make informed decisions, based on toxicokinetic analyses, about the eco-
factors in food animal production. Food products are mandated by federal nomic feasibility of withholding contaminated livestock and milk from the
regulation to be wholesome and safe for the consumer. The Center for market until concentrations of heptachlor fell below tolerance concentra-
Veterinary Medicine (CVM) of the Food and Drug Administration (FDA) tions.
and the Food Safety Inspection Service (FSIS) of the U.S. Department of Because of the large number of inquiries into the system, the idea
Agriculture (USDA) are charged with the responsibility of ensuring that originated that a hard copy version of the pharmacokinetic data would be
human food safety standards are maintained. useful to others without having to access FARAD itself. This is especially true
Drugs are used in food-producing animals for production purposes and for for researchers to whom access to these data will be invaluable and to those
the treatment of disease. Food animals can be exposed to environmental persons outside the U.S. who do not have access to FARAD. The result is the
xenobiotics. Thus, the potential for residues of these substances exists. present handbook.
USDA/FSIS is responsible for monitoring food products for residues of these
materials in food products. Arthur L. Aronson
In 1982, USDA/FSIS, together with the USDA Extension Service (ES), Professor and Head
established the Residue Avoidance Program (RAP). RAP entered into a Department of Anatomy, Physiological Sciences, and Radiology
cooperative agreement with North Carolina State University, Raleigh, the College of Veterinary Medicine
University of California at Davis, and the University of Florida. Gainesville, North Carolina State University
to develop a computer-based system which would provide readily accessible Raleigh. North Carolina
information on drugs, pesticides. and environmental contaminants having
potential to cause residues in food animal tissues. This system is known as the
Food Animal Residue Avoidance Databank (FARAD).
Drs. Jim E. Riviere, Arthur L. Craigmill, and Stephen F. Sundlof have
developed the most comprehensive source of pharmacokinetic information
available on drugs and xenobiotics in food-producing animals. This informa-
tion, constantly updated, is available to veterinarians through regional access
centers for the purpose of preventing residue-contaminated animals and
animal products from entering the human food supply. The data base is
maintained at North Carolina State University, which is the site where all of
PREFACE tion of drug and chemical residue problems in food-producing animals. These
handbooks are a direct outgrowth of this endeavor.
The authors have made every effort to include most of the data available
to them in the open literature; however, it was impossible to include informa-
Residues of drugs and chemicals in the edible tissues of food-producing tion from every article ever published in this field. We apologize in advance
animals are a major public health concern today. In order to address this for missing what some may consider important papers, but time and data
contamination problem in the field and design research studies to help processing limitations dictated certain boundaries. We hope in the future to
eliminate it, a knowledge of drug and xenobiotic pharmacokinetics is essen- continue this compilation. Finally, in any reference of this type, errors in data
tial. This handbook presents a convenient and concise compilation of infor- transcription and analysis will have undoubtedly occurred. We have made
mation pertinent to the application of pharmacokinetic principles to drug and every effort to eliminate them and can only enlist the reader's help in bringing
chemical residue avoidance in the edible tissue and products of animal origin. them to our attention.
The information presented will be of use to veterinarians, toxicologists, phar- The chemicals are divided into three books based on the classification of
macologists, animal scientists, food hygientists, and regulatory personnel the chemical involved. The present handbook contains information on
involved in human food safety. antimicrobial agents as well as an introduction to pharmacokinetic principles.
Included in this and the two companion handbooks which follow are data The companion handbook which follows contains other therapeutic agents
on therapeutic agents, pesticides, growth promotants, and environmental and growth promotants, while a complementing handbook contains pesti-
contaminants to which livestock are often exposed and which may result in cides and environmental contaminants.
food-borne residues. The information is conveniently categorized into four
classes: physiochemical constants, U.S. Food and Drug Administration-
approved preslaughter withdrawal and milk discard times, legal tissue toler-
ances. and pharmacokinetic parameters derived from the open literature. This
is the only publication in which all of this information is available in a single
source. Most of the pharmacokinetic parameters in these volumes have never
been published because the values are a result of statistical analyses per-
formed by the authors on time/concentration data tabulated in the pimary
sources.
The original impetus for compiling the information contained in these
handbooks was the need to develop a central source of those elements
pertinent to residue avoidance. Under the auspices of the U.S. Department of
Agriculture Residue Avoidance Program, the authors established the Food
Animal Residue Avoidance Databank (FARAD), a computerized databank
of regulatory, pharmacologic, and educational information useful for mitiga-
ADVISORY BOARD ACKNOWLEDGMENTS
J. Desmond Baggot The authors wish to express their appreciation to the following people
Veterinary Physiology Department whose assistance with the derivation of data presented in this book was
School of Veterinary Medicine invaluable. and without whom it could not have been written.
University of California California - Ms. Sandy Ogletree, Ms. Dana Ehrnstein, Dr. Iyorlumun
Davis, California Uhaa, Mr. Craig McClean, and Dr. Elaine Fowell.
Florida - Ms. Kandi Crosier, Ms. Patricia Crawley, Ms. Catherine
William Buck Elverston, and Ms. Melissa Rawls. Special thanks is given to Dr. Andrew
College of Veterinary Medicine Beaulieu and Dr. Norman Truner of the U.S. Food and Drug Administration
University of Illinois for their assistance in gathering information on approved veterinary pharma-
Urbana, Illinois ceutics.
North Carolina - Mr. Richard Rogers, Ms. Marianne Tioran, Ms.
Robert Krieger Brenda Nabors, Ms. Patricia Walton, Mr. John Norton, Ms. Donna McLamb,
Veterinary Medicine Department Ms. Julia Hicks. Ms. Karen Miller, Ms. Beth Novak, Dr. Claire Musick, and
W /0 I Regional Program Dr. Gayle Hoyme. We would especially like to thank Ms. Marjorie Locke, the
University of Idaho "keeper ofth e data", for putting order into our lives and for compiling this data
Moscow. Idaho into its present form. We would also like to thank Mr. Mark Cooperstein and
Dr. Steven Toney for software development and Dr. Lynn Dix for develop-
ment of statistical software.
The authors also wish to express their sincere gratitude to Dr. Basil
Eastwood, Dairy Program Director, U.S. Department of Agriculture Exten-
sion Service, for his unfailing support in the development of the Food Animal
Residue Avoidance Databank (FARAD).
TABLE OF CONTENTS Chapter 3
Beta Lactam Antibiotics ......................................................................... 37
Introduction .o .. oooo•o•oo•o•o•oooOOoooooooO•o.oo•o•o•oooooooooo•oooo•o•oooo.oo•o•oo.oo•o•oooo•o•o 37
Selected Readings oO 00.0. 00.0. 00.0 .. 0. 00.0 ... 00 Oo. 00.0. 00.00 00 .. 00 0 00.00. 00 oo oo .. 00 00 00 000.0. 04 0
Chapter I References 0. 00 .. 00 00 oo. Oo 00 00.00 000 ... 00.00 00.0 000 ooo 00.0 0000 00.00 00 00.00 00.0. oo ooo 000 00 00.0. 00.0 40
Principles of Pharmacokinetics ................................................................ I Beta Lactam Structures o•ooOooo .. oooooooOOOOOoooo•o•ooo•o•oooooo•oo•ooooooooooooooooooooooo 45
Introduction ............................. o. . 000 00 00 ooo. 00 Oo. 0. 00 000 00 00 00 .. 00 00 00.00 00 000 00 00 ooo 00. I Table I oooooooooo .. oooo.oOOOOOOOOOOoOOO.oooooo•oo•o•oooooooooooo•ooooooooooooo•oooo•o .. ooooooooooo•o52
Drug Disposition Overview o•o•oooo•o•oooo•o••ooOooooo•ooooooOOOOooooooOOOOoooo•oooooo•ooo 2 Table 2 oooooooooo••oooooo•ooooooooooo ..... oooOOOOoOOO .. ooo•o•ooooooo•oooooooooooo•o•oo.ooooooooooo•o54
Distribution ooo•oooooooooooooooo .. oooooooooooooo•oooooo··oOooooOOOOOooOOOOOoo••o•oooooo•ooooooooooo• 2 Table 2B ooooooo .. OOooooooOoOOOoooooo•o••oooooooooooooo•o•o•ooo•o•o•oooooooooooooo•oo•o•oo•o•oo•o·o58
Elimination 0. 000 00 00 00.00 00 Oo 00 .. 00 00 00.00 ooo 00 00 00.00. 00.0. 00 00.00 00 00 000 00 .. 00 00 00.00 00 00 000 oo. 00 5 Table 3 Ooooo.oooo .. oooooo•oo•ooooooooooo••oooooo•ooooooooo•oooo••o•oooooooooooooooooooooooo.oo•o·o•o59
Renal Mechanisms ·oooooooooooooo•oooooo••oOooooooooooooo•o•ooooo•oooo•o•ooooooooooo• 5 Table 4A •oooo•o··oo•oooo•o•oooooooooo. .. ooooooooooo•oo•o•oooo••ooooooooooo•o•oooo•oooooooooooooooo60
Hepatic Mechanisms 00. oO 0. oo 00.00 00 00. oOO ooo 00 00 000 00 00.0. 00 000.00 00 00.00 0000. oo 00. 6 Table 4B ooooooooooooooooooooooooooooooooooooooooooooooooooooooooooo.oooooooooooooo.o ...... oooooollO
Absorption . oo 00.0 ooo 00.00 00 Oo. 00.000 0o oO 00. Oo 00 00 00.00. 00 oo 000 00.00 00 00.0. 00 000 00.00 00.0. 00 000 oo 00 08
Pharmacokinetics 00 oOO 0. .. 000 000.0. oo 00 ooo 00 00.00 0000 0. 00 00 000 00 00.0. 00 ooo 00.00 00.0000 00.00 oo 00 08 Chapter4
Compartmental Systems 0. 000 0oO O 00 ooo 00 00.00 00 .. 0o o 000 000 00 00 00.00 00 .. 00 00 00 000 00 00.00 oo. 0. 9 Tetracycline Antibiotics ........................................................................ 175
Multiple Dose Administration o.. ooooooooooooo .. ooo .. ooooooo .. ooooooooooooooooooooooooo 15 Introduction oooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooooOooo•ooooooooooo 175
Extravascular Drug Administration oooooooo .... o.. oooooooo.ooooooooooooooooooooooooo 17 Selected Readings ooooooooooooooooooooooooooooo•ooooooooo••oooo·o•oooo•o•ooooooo•oo•ooo•oo•o 176
Statistical Considerations o.. 00 oo o.. 00 o. ... 00 00 ...... 00 o.. 00 0.. 00 .. oooOo 0.. 00 o. ..... o.. oo 01 9 References oooooooooo,ooooooooo•o•oo•o•ooooo•oOOooo .. ooo ... oo .. o•oo.o.oooo•oooo.oooo•oo•ooooooool76
Principles of Interspecies Extrapolation .. ooooooooooooooooooooooooooooooo ...... ooo 22 Tetracycline Structures OoOOOOOoo•oooooooooooooo•o•oooo .. ooooooooOOoooooooo•oooooooooooooo 180
References . oo 0000.00 00 00.00 ... 00 000 00 ooo 00 ooo 00 00 00.00 000 oo. 0000 000 0. 00 00.00. 00 00.00 00 000 00 000 oo 02 7 Table 1 oooooooooooooo•o.ooooooo•o•ooooooooooooooO•o•oooo•oooooooooooo.ooooooooooo.oooo•ooooo•oooool82
Table 2 Ooooooooooooooooooo•oooooo•oo•o,ooooooOooOooo•ooooOooooo000000oo.oooo•o•ooooooo•oo•oooooooo183
Chapter 2 Table 3 oooooooooooooo•o.,o.oooo•o·oooo,ooooooo.oo•ooooooooo•o•oo•oo•ooooooooooo•oooooo•oo•oo•oooool88
Orientation to Chapters and Tables ...................................................... 29 Table 4A 0. 00 00 00 .. 00 ooo 00 00.00 00.0 00.00 .. 00.0 00.00 ... 00 00 00. ooo 00 00.00 00000 00.00 00 0000 00 00.00 000 190
Table I Oo000oooooo•oooooo•o•ooo.oooooo•oooo•o•oooo•oooooo••oooo•oooooooooo•oooooooo•o•ooooooooooooo.29 Table 4B oooooooo••oooo,o•oooooooooooooo••oo•oooooo•o.oooooooooo•o•ooooooooo ... oo•o•ooooooooooooo2!0
Table 2 oooooooooooooooo•o•oo.o.oooooooooooOOOOoooo•oooooo .. oooo•oooooo•o•o•oooooooooo•o•ooooooooooo.29
Table 3 ooo•oo.oooo•oooooo•oooo,oooooooooooooooooooooooo•oo•oooooo•oo•oooooooooooooo•o•ooooooooooo·o·29 Chapter 5
Table 4 OoOooo•oo•oooo.ooOoOOOOooooo••oo•o•ooooooooooooooo•ooooo•o•oooo•oooooo.ooooo•o•ooooooooooo.oo30 Macrolide Antibiotics ........................................................................... 229
Statistical Methods oo•oooooooooo•oooooooo•oo•ooooooooo•o•oooo•oooooo•o•oooooooooooo•oooooo•o· 31 Introduction 0. 00 .. 0o o. 00 000 0000.00 oo 00 .. 00 00.00 00 00.00. 0. 00 Oo. 00. oo Oo 00.00 00.00 00.000 00.00 00 000 229
Pharmacokinetics Equations ooOOOOoooooooooooooooooooooo•oooo•oooooo•ooooo•o•o•oo.oooooo 33 Table 1 Oooo•o•oo.o••oo•o·ooooooo•o•oooo.ooooooooooooooooooooOOoo••OOOoooo·o·o•oooo•ooooooo•oooo•oo230
Abbreviations to Tables OOOOOooooOOOOooooOOOOOOoOOoOooooo•oo•ooooo•ooooooo•oo•ooo•ooooooo•o 33 Selected Readings 00 0.00 00 00.00 oo .... 00 00.00 00 00.00 00.0000 .. 00 Oo 00.00 00.00 00. Oo 000.00 00 00.00 230
Routes of Administration Ooooooooooooo ...... o.. ooooooooooooo .... ooooooOooooooOOO 33 References 000.00.00 ooo 00 00.00 00.00 oo 00 .. 00.0000 00. Oo 00 000 00 00 .. 00 oo 00000 00.00 00 00.000 00.0. 00.00 230
Species Codes 0o o. 0. 0. .. 0. 00 00 00 000 00.00 0. 00 .. 0. 00 00 00.00 00.0. 0. 00 .. 0.. 00 0 00. Oo. 0. 00.0 34 Macrolide Structures •oooo•o•ooooooooOOoOOOO ... oooo•oo.ooooooo.oooo•o•ooooooo.ooooo•o•oooo 232
Breeds .oooo·o•ooooooooo•o•·oo,oooOoo•oooo•O•oooo .. Ooo•oo•oooo•ooo•oooo••o•o•oo•o•oo•ooo.oo35 Table 2 ... o.oooo.ooooo•o.ooooooo•o•oooo.ooooooo.oo•o•oooooo•oooo•oo···oo•o·oo•o•oo•oooooooooooo•oo235
Table 3 ........................................................................................... 244 References ..................................................................................... 340
Table 4A ........................................................................................ 246 Sulfonamide Structures ................................................................. 344
Table 4B ........................................................................................ 254 Table I ........................................................................................... 348
Table 2 ........................................................................................... 349
Chapter 6 Table 3 ........................................................................................... 355
Aminoglycoside Antibiotics .................................................................. 263 Table 4A ........................................................................................ 356
Introduction ................................................................................... 263 Table 4B ........................................................................................ 378
Selected Readings .......................................................................... 265
References ..................................................................................... 266 Chapter 8
Aminoglycoside Structures ........................................................... 271 Miscellaneous Antimicrobial Agents ................................................... 409
Table I ........................................................................................... 275 Introduction ................................................................................... 409
Table 2 ........................................................................................... 276 Selected Readings .......................................................................... 410
Table 3 ........................................................................................... 279 References ..................................................................................... 411
Table 4A ........................................................................................ 280 Miscellaneous Structures ............................................................... 415
Table 4B ........................................................................................ 308 Table I ........................................................................................... 421
Table 2 ........................................................................................... 423
Chapter 7 Table 3 ........................................................................................... 433
Sulfonamides .......................................................................................... 339 Table 4A ........................................................................................ 434
Introduction ................................................................................... 339 Table 4B ........................................................................................ 482
Selected Readings .......................................................................... 340 Index ............................................................................................. 525

1
Chapter 1 occasionally drugs must be used at "extralabel" doses, in nonapproved
species, or are used inadverdently at excessive dose levels. Sometimes
management conditions or disease may also alter drug disposition to the point
PRINCIPLES OF
that the withdrawal time should be lengthened. In other cases, chemicals from
the environment may enter the food-producing animal, in which instances,
PHARMACOKINETICS
approved withdrawal times and milk discard times do not exist. It is then the
task of the veterinarian to estimate a safe withdrawal time or, alternatively,
recommend that the animals be disposed of rather then be marketed for human
INTRODUCTION consumption.
The information required to estimate when a drug or chemical is
Pharmacokinetics is the study of the time course of drug and xenobiotic depleted from the animal to safe levels is in the realm of the discipline of
concentrations in the body. The purpose of this section is to provide an pharmacokinetics. Pharmacokinetic parameters also allow one to determine
overview of basic pharmacokinetic principles so that the data tabulated in the tissues in which drugs distribute or accumulate. If data have been collected in
remainder ofthe text will be useful. This handbook is a compilation in a single both healthy and diseased animals, then one may even be able to predict what
source of as much of the data as is available on the pharmacokinetics and effect a disease process may have on drug or chemical depeltion times. If these
disposition of drugs and xenobiotics encountered in veterinary medicine. data on the rate and extent of depletion of drugs or chemicals in the body are
The impetus for compiling this volume was to generate data which would reduced to a few basic pharmacokinetic parameters, then the information may
be useful for avoiding drug residues in the edible tissues and products of be extrapolated to individual field situations. Pharmacokinetics also sheds
animals.23·-'0 When drugs are administered to food producing animals either as light on the question of interspecies extrapolations. The problem facing the
growth promotors or for therapeutic reasons, a specified period of time must field veterinarian and regulatory personnel is that these data are generally not
elapse after cessation of drug administration and before slaughter to allow readily available. In addition, although "raw" depletion data may appear in
depletion of drug to occur from the animal's body to levels that are considered the published literature, all that is generally tabulated is drug concentrations
''safe" for the human consumer of edible products. These are referred to as the in different tissues as a function of time after drug administration. Unless
"withdrawal time" for meats and the "milk discard time" for dairy products. these data are analyzed and relevant pharmacokinetic parameters determined,
In the U.S., the official withdrawal and milk discard times are determined there is little possibility of extrapolating to the field problem at hand. It was
prior to marketing by the Food and Drug Administration based on data thus the purpose of this handbook to compile this information so that the
submitted by the manufacturer of the product. These times are thus dependent relevant pharmacokinetic parameters would be readily available to the
upon the specific formulation of the product as well as on the approved uses veterinarian, regulatory personnel, or researcher involved in mitigating these
and methods of administration, and in most cases, these tests are conducted problems.
in healthy animals. The target concentrations which are deemed safe for The data sources for this compilation are from the open published
human consumption are set as "tissue tolerances" by the Food and Drug literature. Where available, pharmacokinetic parameters calculated by the
Administration. When drugs are used in the approved manner in approved authors of the primary literature are utilized. However, in many cases,
species, these legal withdrawal times are generally sufficient. However, pharmacokinetic parameters were not available as data in the articles con-